A Site of Vulnerability on the Influenza Virus Hemagglutinin Head Domain Trimer Interface

Cell. 2019 May 16;177(5):1136-1152.e18. doi: 10.1016/j.cell.2019.04.011.

Abstract

Here, we describe the discovery of a naturally occurring human antibody (Ab), FluA-20, that recognizes a new site of vulnerability on the hemagglutinin (HA) head domain and reacts with most influenza A viruses. Structural characterization of FluA-20 with H1 and H3 head domains revealed a novel epitope in the HA trimer interface, suggesting previously unrecognized dynamic features of the trimeric HA protein. The critical HA residues recognized by FluA-20 remain conserved across most subtypes of influenza A viruses, which explains the Ab's extraordinary breadth. The Ab rapidly disrupted the integrity of HA protein trimers, inhibited cell-to-cell spread of virus in culture, and protected mice against challenge with viruses of H1N1, H3N2, H5N1, or H7N9 subtypes when used as prophylaxis or therapy. The FluA-20 Ab has uncovered an exceedingly conserved protective determinant in the influenza HA head domain trimer interface that is an unexpected new target for anti-influenza therapeutics and vaccines.

Keywords: B-lymphocytes; antibodies; antibody-dependent cell cytotoxicity; antigen-antibody reactions; hemagglutinin glycoproteins; influenza A virus; influenza virus; monoclonal; viral.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Murine-Derived / immunology*
  • Antibodies, Viral / immunology*
  • Dogs
  • Epitopes / immunology*
  • Hemagglutinin Glycoproteins, Influenza Virus / immunology*
  • Influenza A virus / immunology*
  • Influenza Vaccines / immunology*
  • Madin Darby Canine Kidney Cells
  • Mice
  • Orthomyxoviridae Infections* / immunology
  • Orthomyxoviridae Infections* / pathology
  • Orthomyxoviridae Infections* / prevention & control

Substances

  • Antibodies, Monoclonal, Murine-Derived
  • Antibodies, Viral
  • Epitopes
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Influenza Vaccines